The mapping of the human genome, completed in 2003, launched a new era marked by growth in the development of diagnostic tests designed for use with new drugs. As of 2009, some 40 drugs were accompanied by these companion tests.
Now FDA is weighing in, saying it wants to assure patients that the companion diagnostics are as safe and effective as the drugs that they accompany. On July 14, the agency issued a draft guidance designed to inform companies about the agency’s policy for reviewing companion diagnostics and their corresponding therapy.
FDA’s “Draft Guidance for Industry and Food and Drug Administration Staff - In Vitro Companion Diagnostic Devices” recommends that diagnostic manufacturers meet with agency professionals early in their development process to ensure that FDA’s expectations are included in development plans. The draft guidance also emphasizes FDA’s intent to review drugs and their corresponding companion diagnostics simultaneously.
The proposed rule also identifies instances where the FDA may approve a targeted medicine in the absence of a cleared companion diagnostic—namely in cases where a therapy is intended to treat a serious or life-threatening disease for which there is no “available or satisfactory treatment” as well as cases when the potential benefits are deemed by the agency to outweigh the risks of not having an approved companion diagnostic. In such cases, according to FDA, the therapy could be approved first while the companion diagnostic may be sanctioned later.
FDA “strongly encourages sponsors to time their clinical developments and premarket submissions to facilitate concurrent approval,” according to the draft guidance. “We are not looking to slow down development. Rather we believe that if stakeholders understand the regulatory requirements, development and approval will be sped up,” Elizabeth Mansfield, Ph.D., director, personalized medicine in the Office of In Vitro Diagnostics in FDA’s Center for Devices and Radiological Health, told GEN.
Dr. Mansfield said the draft guidance does not signify a change by FDA in how it plans to regulate companion diagnostic devices going forward: “We are not expecting to change our approach. This guidance is intended to let stakeholders know what our favored approach is so that their expectations are matched to the regulatory approach.”
FDA had sought to issue guidelines addressing aspects of drug/diagnostic co-development since 2005, when the agency issued a concept paper outlining its initial thinking on the topic. That effort was criticized by both pharmaceutical firms and test makers, both of which felt the agency’s proposed guidelines failed to account for the challenges of aligning competing interests, different development timelines, and divergent regulatory pathways for therapeutics and diagnostics.
Harry Glorikian, managing partner with Scientia Advisors, cautions that if the FDA ultimately requires that a diagnostic be approved and in kit form before a drug is approved, that test has to be ready for use before Phase III trials, since the FDA must be able to look at data in which patients are stratified using the exact same technology in clinical trials that will be used once the drug is on the market.
“This implies that there will be an even greater hurdle to drugs being developed for launch with a companion diagnostic, and pharma companies will be even more reluctant to take this path,” Glorikian told GEN. “Ultimately, it will result in a net increase in the time and cost of drug development.”
Diagnostic companies may find it much harder to develop joint programs with pharma partners. They may no longer consider providing a better test after a drug is launched as a viable business model. Additionally, diagnostic firms will be required to codify all technical features into a kit, potentially limiting diagnostic innovation.
Getting Agency Centers to Work Together
Not all industry observers share that sentiment. “We view the new draft guidance as a clear indication of FDA’s interest in streamlining the approval process for companion diagnostics,” concluded Brian Marckx, an analyst with Zacks Equity Research, in a report.
Also weighing in on FDA’s draft guidance is the Personalized Medicine Coalition (PMC), an umbrella organization that represents more than 200 academic, industry, patient, provider, and payer communities. Amy M. Miller, Ph.D., PMC’s public policy director, told GEN that the draft guidance provides clarity on FDA’s current thinking on regulating companion diagnostics, long a source of concern to the drug and device industries.
In its draft guidance, FDA envisions collaboration between its drug and device centers but does not offer specifics. “There’s very little detail about how that’s going to actually work. If that works well, it will speed up clearance of these products. But if that does not work well, it could slow it down,” Dr. Miller pointed out.
In its 2009 report “The Case for Personalized Medicine,” PMC said more than 1,300 genetic tests exist that signal inherited susceptibility to a wide range of conditions: “While not every test has a therapeutic option, a genetic diagnosis often permits targeted prevention or mitigation strategies.” Dr. Miller said the report is being updated, with the new edition—including new data—set to be published in the fall.
Sometimes, even simultaneous approval of a drug and its companion diagnostic is no guarantee that problems won’t arise later. In 2009, FDA updated the labeling for two colorectal therapies already on the market, Vectibix (Amgen) and Erbitux (Eli Lilly and subsidiary ImClone), to inform doctors that patients with KRAS mutations would not respond to these drugs.
Vectibix and Erbitux are anti-epidermal growth factor receptor (EGFR) antibodies approved at the same time with their original companion diagnostic, developed by partnering with Danish firm DAKO. But evidence that KRAS mutation status would affect how subjects responded to anti-EGFR treatments became apparent only after the decisive clinical trials for these antibodies were conducted. Amgen and Imclone analyzed the existing retrospective information, finding that about 43% of patients—those with KRAS mutations—did not respond to the EGRF inhibitors.
Qiagen’s DxS subsidiary later signed agreements with both drug companies to develop a KRAS companion test for Vectibix and Erbitux and pursue approvals from FDA for those tests along with the drug developers. FDA to date has yet to approve Qiagen’s KRAS test. In the meantime, a number of laboratories are marketing tests that detect KRAS mutations but have not been cleared through the agency.
Concurrent Dx/Rx reviews have the potential to bring promising new drugs and their companion diagnostics to market faster. But for that to happen, drug and diagnostics companies will need to consult with FDA earlier in the development process.
Just as diagnostic firms will have to work closely with drug developers, so will the drug and device centers at the FDA. How much progress is made toward goals set by the agency will determine how effective the concurrent Dx/Rx review process telegraphed by FDA in its Draft Guidance will be in bringing life-saving therapeutics and diagnostics to the patients who need them.